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Biomedical subjects

E E Ladenheim

Publications and source records attributed to E E Ladenheim.

At least 19 recordsLinked to original sources
PubMed2003

Ethanol consumption and serotonin-1A (5-HT1A) receptor function in heterozygous BDNF (+/-) mice.

Heterozygous brain-derived neurotrophic factor (BDNF) (+/-) mice display abnormalities in central serotonergic neurotransmission, develop decrements in serotonergic innervation of the forebrain, and exhibit enhanced intermale aggressiveness. As disturbances of serotonin neurotransmission are implicated in alcohol abuse and aggression, we have examined in BDNF (+/-) mice alcohol drinking behavior, as well as central 5-hydroxytryptamine (5-HT)1A receptor function at the level of 5-HT1A receptor-G protein interaction. BDNF (+/-) mice displayed increased ethanol intake in a two-bottle choice procedure. There was no difference in the preference ratio for non-alcoholic tastants (i.e. quinine or saccharin) between genotypes. In the brains of alcohol-naive mice, we measured [35S]GTP gamma S binding stimulated by the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-dipropyl-aminotetralin hydrobromide (8-OH-DPAT; 1 microM). In BDNF (+/-) versus wild-type (WT) mice, 5-HT1A receptor-stimulated [35S]GTP gamma S binding was significantly attenuated in the median raphe nucleus. There was a decrease in (+/-)8-OH-DPAT-stimulated [35S]GTP gamma S binding in the dorsal raphe, which did not reach statistical significance. In the hippocampus, 5-HT1A receptor-stimulated [35S]GTP gamma S binding was significantly attenuated in BDNF (+/-) mice. 5-HT1A receptor-stimulated [35S]GTP gamma S binding was attenuated in the anterior cingulate cortex and lateral septum, although these reductions did not reach statistical significance. 5-HT1A receptor number was not different between genotypes in any area of brain examined, suggesting that 5-HT1A receptor function, specifically the capacity of the 5-HT1A receptor to activate G proteins, is attenuated in BDNF (+/-) mice.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2002

Disruptions in feeding and body weight control in gastrin-releasing peptide receptor deficient mice.

Bombesin (BN) interacts with two mammalian receptor subtypes termed gastrin-releasing peptide (GRP)-preferring (GRP-R) and neuromedin B (NMB)-preferring (NMB-R) that may mediate the satiety action of BN. We examined the feeding behavior of mice that were deficient in the GRP-R (GRP-R KO) to assess the overall contribution of this receptor subtype in the feeding actions of BN-related peptides. GRP-R KO mice failed to suppress glucose intake in response to systemically administered BN and GRP(18-27), whereas both peptides elicited a potent reduction of intake in wild-type (WT) mice. Neither GRP-R KO nor WT mice suppressed glucose intake following NMB administration. Unlike the impaired responses to BN-like peptides, the feeding inhibitory action of cholecystokinin was enhanced in GRP-R KO mice. Consistent with behavioral results, GRP-R KO mice also exhibited a reduction in c-Fos immunoreactivity in the nucleus of the solitary tract (NTS) and paraventricular nucleus (PVN) following peripheral administration of BN. An evaluation of meal patterns showed that GRP-R KO mice ate significantly more at each meal than WT mice, although total 24 h food consumption was equivalent. A long-term analysis of body weight revealed a significant elevation in GRP-R KO mice compared with WT littermates beginning at 45 weeks of age. These data suggest that the GRP-R mediates the feeding effects of BN-like peptides and participates in the termination of meals in mice.

Animals↗
PubMed2001

Reduced gastrin releasing peptide in cerebrospinal fluid after recovery from bulimia nervosa.

People with anorexia (AN) and bulimia nervosa (BN) have altered patterns of eating. It is possible that alterations of the neuropeptide gastrin releasing peptide (GRP), a bombesin (BBS) -like peptide with potent central anorexigenic activity, could contribute to disturbed eating behavior. To avoid the confounding effects of pathologic eating behavior, we measured cerebrospinal fluid (CSF) GRP concentrations in women who were long-term recovered (>1 year, normal weight, and regular menstrual cycles, no binging or purging) from AN (REC AN, N=12) or BN (REC BN, N=21) compared to healthy control women (NC, N=15). CSF GRP was significantly lower (chi(2)=9.41(3), p<0.01) in REC BN (9.6+/-3.1 pg/ml) compared to NC (13.4+/-5.5 pg/ml) and REC AN (11.6+/-2.9 pg/ml). Persistent GRP abnormalities after recovery from BN raise the possibility that this alteration might be trait-related and contribute to episodic hyperphagia in BN.

Adult↗
PubMed2001

Leptin amplifies the feeding inhibition and neural activation arising from a gastric nutrient preload.

Leptin affects food intake by reducing meal size, suggesting that it may modulate the efficacy of within-meal satiety signals. To assess whether leptin would amplify the feeding inhibitory actions of a nutrient gastric preload, we compared liquid diet food intake and patterns of c-Fos activation in response to intraventricular leptin (3.5 microg), intragastric Ensure (10 ml over 10 min), or their combination. Leptin alone did not affect Ensure intake but significantly increased the suppression of intake produced by the intragastric preload. Within the nucleus of the solitary tract (NTS), leptin alone did not stimulate c-Fos but significantly elevated the number of c-Fos positive cells in response to intragastric Ensure at medial and rostral levels. Within the paraventricular nucleus (PVN), both leptin and the gastric load stimulated c-Fos expression, but the combination resulted in significantly greater number of c-Fos positive cells. These data demonstrate that leptin modulates the feeding inhibition produced by meal-related signals and suggest that this modulation occurs at the levels of the NTS and PVN.

Animals↗
PubMed2001

Within-meal gut feedback signaling.

During a meal, multiple gastrointestinal sites are stimulated by ingested nutrients and their digestion products, initiating local gastrointestinal actions and producing a variety of potential feedback signals that can contribute to meal termination. During ingestion, gastric emptying is rapid, allowing a significant portion of ingested nutrients to enter the intestine. Gastric and duodenal vagal afferent fibers increase their electrophysiological activity in relation to the mechanical presence of ingested nutrients. On reaching the duodenum, nutrients also activate vagal chemosensitive elements and stimulate the release of a variety of brain gut peptides including cholecystokinin (CCK). CCK also activates vagal afferent fibers directly and modifies the response properties of vagal mechanosensitive fibers to gastric and duodenal loads. Blocking or eliminating these feedback signals results in increased meal size demonstrating their role in meal termination.

Afferent Pathways↗
PubMed2001

A role for NPY overexpression in the dorsomedial hypothalamus in hyperphagia and obesity of OLETF rats.

Otsuka Long-Evans Tokushima Fatty (OLETF) rats lacking CCK-A receptors are hyperphagic, obese, and diabetic. We have previously demonstrated that these rats have a peripheral satiety deficit resulting in increased meal size. To examine the potential role of hypothalamic pathways in the hyperphagia and obesity of OLETF rats, we compared patterns of hypothalamic neuropeptide Y (NPY), proopiomelanocortin (POMC), and leptin receptor mRNA expression in ad libitum-fed Long-Evans Tokushima (LETO) and OLETF rats and food-restricted OLETF rats that were pair-fed to the intake of LETO controls. Pair feeding OLETF rats prevented their increased body weight and elevated levels of plasma insulin and leptin and normalized their elevated POMC and decreased NPY mRNA expression in the arcuate nucleus. In contrast, NPY expression was upregulated in the dorsomedial hypothalamus (DMH) in pair-fed OLETF rats. A similar DMH NPY overexpression was evident in 5-wk-old preobese OLETF rats. These findings suggest a role for DMH NPY upregulation in the etiology of OLETF hyperphagia and obesity.

Age Factors↗
PubMed2001

Intracerebroventricular CART peptide reduces food intake and alters motor behavior at a hindbrain site.

Peptides from cocaine- and amphetamine-regulated transcript (CART) reduce food intake in rats when injected into the lateral ventricle. Hypothalamic and hindbrain sites important in the control of feeding contain CART-immunoreactive fibers. To further define the site of CART's anorectic action, we compared feeding and other behavioral responses to third or fourth ventricular (3V, 4V) CART-(55-102) in 6-h food-deprived rats, both before and after cerebral aqueduct occlusion. 3V CART reduced the volume of Ensure consumed and resulted in fewer observations of eating and grooming within the 30-min test session. These reductions were significantly attenuated by aqueduct obstruction. 4V CART suppressed Ensure intake and resulted in decreased observations of feeding both with and without aqueduct blockade. 3V CART produced flat-backed postures and movement-associated tremors that were prevented by aqueduct obstruction. 4V CART also produced these signs, both with and without aqueduct blockade. We conclude that the major hypophagic effect of intracerebroventricular CART is mediated at a hindbrain site. The association of CART-induced feeding suppression with altered motor behavior questions the specificity of intracerebroventricular CART for actions on feeding.

Animals↗
PubMed1999

Inhibition of gastric emptying by bombesin-like peptides is dependent upon cholecystokinin-A receptor activation.

The amphibian peptide bombesin (BN) and the related mammalian peptides gastrin-releasing peptide (GRP) and neuromedin B (NMB) inhibit gastric emptying in rats. Exogenous administration of BN stimulates the release of cholecystokinin (CCK), a gastrointestinal peptide that also potently inhibits gastric emptying. To determine whether the inhibition of gastric emptying by BN-like peptides is mediated by a CCK-dependent mechanism, we examined the ability of the CCK-A receptor antagonist, devazepide, to block the inhibition of saline gastric emptying produced by BN, GRP18-27 and NMB. Using the same dosages as in the gastric emptying experiment, we also evaluated the effect of devazepide on feeding suppression produced by systemically administered BN. Our results showed that devazepide completely blocked the suppression of gastric emptying produced by BN, GRP18-27 and NMB but had no effect on BN-induced suppression of food intake. These results suggest that BN-like peptides inhibit gastric emptying through an indirect mechanism that is dependent upon CCK-A receptor activation. In contrast, the suppression of food intake by BN, in this experimental paradigm, is independent of CCK-A receptors.

Animals↗
PubMed1999

Central leptin modulates behavioral and neural responsivity to CCK.

The mechanisms through which leptin, the protein product of the ob gene, affects food intake remain to be determined. To assess whether the actions of leptin depend on modulation of within-meal satiety signals, we measured the effect of third ventricular leptin administration on the satiety actions of CCK. Leptin (10 micrograms) administered 1 h before 30-min access to a liquid diet had no effect on intake when administered alone, but doses of 3.5 or 10 micrograms dose dependently increased the suppression of intake produced by 1 nmol/kg CCK. Examination of patterns of c-Fos activation induced by 3.5 micrograms leptin and 1 nmol/kg CCK revealed that the combination produced significant c-Fos activation within the area postrema and the caudal and medial nucleus of the solitary tract (NST) compared with either leptin or CCK treatments alone. The leptin-CCK combination also resulted in increased c-Fos activation within the paraventricular nucleus of the hypothalamus above that produced by leptin alone. These data suggest that the actions of leptin in food intake are mediated through its ability to modulate responsivity to within-meal satiety signals.

Animals↗
PubMed1998

Loss of bombesin-induced feeding suppression in gastrin-releasing peptide receptor-deficient mice.

The gastrin-releasing peptide receptor (GRP-R) is one of three members of the mammalian bombesin subfamily of seven-transmembrane G protein-coupled receptors that mediate diverse biological responses including secretion, neuromodulation, chemotaxis, and growth. The X chromosome-linked GRP-R gene is expressed widely during embryonic development and predominantly in gastrointestinal, neuronal, and neuroendocrine systems in the adult. Surprisingly, gene-targeted mice lacking a functional GRP-R gene develop and reproduce normally and show no gross phenotypic abnormalities. However, peripheral administration of bombesin at dosages up to 32 nmol/kg to such mice had no effect on the suppression of glucose intake, whereas normal mice showed a dose-dependent suppression of glucose intake. These data suggest that selective agonists for the GRP-R may be useful in inducing satiety.

Amylases↗
PubMed1997

Characterization of bombesin binding sites in the rat stomach.

We characterized the bombesin receptor population in the rat stomach and determined the receptor subtype mediating the contractile effect of bombesin in the gastric fundus. Using in vitro receptor autoradiography, we evaluated the ability of the specific gastrin-releasing peptide-preferring receptor antagonist [D-F5,Phe6,D-Ala11]bombesin-(6-13) methyl ester to inhibit binding of 125I-[Tyr4]bombesin to the gastric fundus, corpus and antrum. Binding to these regions was completely inhibited by [D-F5,Phe6,D-Ala11]bombesin-(6-13) methyl ester suggesting that these receptors are the gastrin-releasing peptide-preferring subtype. We found that the rank order of potency for the contractile effect of bombesin, and the related mammalian peptides neuromedin C and neuromedin B, was bombesin > neuromedin C > neuromedin B. [D-F5,Phe6,D-Ala11]bombesin-(6-13) methyl ester was equipotent in antagonizing contractions produced by all three peptides. Furthermore, receptor tachyphylaxis to either neuromedin C or neuromedin B abolished the subsequent contractile response elicited by neuromedin C and neuromedin B, suggesting that one bombesin receptor subtype mediates rat gastric fundal contractions. Together, these results demonstrate that the bombesin receptor subtype in the rat stomach is gastrin-releasing peptide-preferring subtype and that this subtype is responsible for the effects of bombesin-like peptides on fundal smooth muscle contraction.

Animals↗
PubMed1997

Caudal hindbrain neuromedin B-preferring receptors participate in the control of food intake.

Recent studies have identified two subtypes of bombesin (BN) receptors in the rat central nervous system: gastrin releasing-peptide (GRP) preferring and neuromedin B (NMB) preferring. To investigate a role for the NMB-preferring receptor subtype in feeding suppression elicited by fourth ventricular (4V) BN administration, we evaluated the ability of a selective NMB-preferring receptor antagonist, BIM-23127, to block suppression of glucose intake produced by 4V BN (10 pmol). Our results showed that 4V administration of BIM-23127 dose dependently antagonized the suppression of glucose intake produced by 4V BN. In addition, 4V administration of BIM-23127 alone increased glucose intake above that observed in the baseline condition. These results support a role for the NMB-preferring BN receptor subtype in the suppression of intake produced by 4V BN administration and suggest that endogenously released NMB participates in ingestive control.

Animals↗
PubMed1997

Relationships between gastric motility and gastric vagal afferent responses to CCK and GRP in rats differ.

The brain-gut peptides cholecystokinin (CCK) and the mammalian bombesin-like peptide gastrin-releasing peptide (GRP) suppress food intake. Vagotomy blocks CCK- but not bombesin (BN)-induced feeding suppression, demonstrating differential vagal contributions. We examined the relationship between the ability of CCK and the active fragment of GRP, GRP-(18-27), to stimulate gastric vagal afferent activity and their ability to elicit changes in gastric motility. We also examined ligated cervical vagal segments and revealed specific 125I-CCK vagal binding without evidence of radiolabeled BN binding sites. Both close arterial and intraperitoneal CCK and GRP-(18-27) produced dose-dependent increases in activity in gastric vagal mechanoreceptive afferents. CCK dose dependently decreased gastric pressure without altering antral wall tension, whereas GRP-(18-27) dose dependently increased both gastric pressure and peak antral wall muscle tension. These results suggest that GRP-(18-27) activates gastric vagal afferents secondary to its stimulation of gastric motor effects. CCK activates this same population of vagal afferents independent of changes in gastric tension, suggesting a direct action of CCK at functional vagal CCK receptors.

Animals↗
PubMed1996

Receptor subtype mediation of feeding suppression by bombesin-like peptides.

Bombesin (BN) and the related mammalian peptides gastrin-releasing peptide (GRP), neuromedin C (NMC), and neuromedin B (NMB) suppress food intake in rats. Recent studies show two distinct receptor subtypes, GRP-preferring and NMB-preferring. BN interacts equally with both subtypes raising the possibility that one or both subtypes mediate the reduction of feeding by BN. To examine this issue, we compared suppression of intake produced by dose ranges (0-100 nmol/kg) of BN, GRP, NMC, and NMB and acetylated NMC and NMB. We found that all peptides elicited dose-dependent reductions of intake with overall differences in potency and efficacy. At intermediate doses, the rank order of potency for suppression was BN = AcNMC > NMC = GRP > NMB = AcNMB; however BN, GRP, and NMC were equipotent at the lowest and highest doses. Coadministration of NMC or GRP and NMB produced suppressions above that of either peptide alone and equivalent to BN. Taken together, these data support a role for both receptor subtypes in the suppression of food intake by BN and BN-like peptides.

Animals↗
PubMed1996

Hindbrain GRP receptor blockade antagonizes feeding suppression by peripherally administered GRP.

Bombesin (BN)-like peptides injected peripherally or centrally suppress food intake in rats. The relationship between the central and peripheral actions of BN is unknown. However, experimental evidence supports a critical role for the caudal hindbrain in mediating the feeding effects of BN. To investigate this relationship further, we examined the ability of fourth ventricular infusion of a specific gastrin-releasing peptide (GRP) antagonist, [D-F5, Phe6, D-Ala11]BN-(6-13) methyl ester (BN-ME), to block suppression of glucose intake (0.5 kcal/ml) produced by intraperitoneal administration of GRP-(18-27) in 5-h food-deprived male Sprague-Dawley rats (n = 10). We found that fourth ventricular administration of 10, 32, and 100 ng BN-ME blocked the suppression of glucose intake produced by peripherally administered 10 nmol/kg GRP-(18-27). The most effective dose of BN-ME (100 ng) blocked the ability of peripheral injection of GRP-(18-27) to inhibit glucose intake but had no effect on intake when given alone. These results demonstrate that the availability of caudal hindbrain GRP receptors is necessary for peripherally administered GRP-(18-27) to reduce food intake in rats.

Animals↗
PubMed1996

Bombesin and cholecystokinin differentially affect ingestive microstructural variables whether given alone or in combination.

The ability of dose combinations of cholecystokinin (CCK) and bombesin to inhibit liquid glucose (0.125 gm/ml) intake and affect microstructural components of ingestive behavior in rats was examined. Five minutes before access to the glucose solution, rats were injected with dose pairs of CCK and bombesin. Both CCK and bombesin inhibited intake in a dose-related fashion. The magnitude of the inhibition produced by dose combinations was never greater than the sum of the inhibitions produced by the individual doses. CCK and bombesin affected different microstructural components of ingestion. CCK reduced burst size and cluster size, whereas bombesin reduced burst number and cluster number. These effects of the 2 peptides were not altered by the presence of the other peptide. These results suggest that different mechanisms of action underlie the feeding inhibitory actions of the 2 peptides.

Animals↗
PubMed1994

Blockade of feeding inhibition by neuromedin B using a selective receptor antagonist.

The ability of a selective neuromedin B receptor antagonist, D-Nal-cyclo[Cys-Tyr-D-Trp-Orn-Val-Cys]-Nal-NH2 (BIM-23127), to block suppression of food intake produced by the mammalian bombesin-like peptides neuromedin B and neuromedin C was examined. BIM-23127 completely blocked suppression of intake produced by neuromedin B but not by neuromedin C. These results suggest an independent role for neuromedin B receptors in suppression of food intake by bombesin-like peptides and demonstrate the utility of this group of antagonists for in vivo experiments.

Animals↗